Systematic Review of Dexketoprofen in Acute and Chronic Pain

R. Andrew Moore; Jodie Barden

Disclosures

BMC Clin Pharmacol 

In This Article

Results

Thirty-five trials were found in acute and chronic pain, 32 of which had reporting quality of 3/5 or better and 30 of which had OPVS score of at least 9/16 ( Table 1 ). Ten trials had individual group sizes of 100 patients or more. The total number of patients was 6,380, of whom 3381 received dexketoprofen ( Table 1 ). More patients were in trials of oral therapies (4,249 total, 2,270 on dexketoprofen) than trials of intramuscular or intravenous therapies (2,131 total, 1,111 on dexketoprofen). Information from 16 trials (46%) with 3,253 patients (51%) was obtained from clinical trial reports from previously unpublished trials, or trials published only as abstracts. All 16 clinical trial reports had a quality score of at least 3/5 and an OPVS score of at least 9/16. Almost all of the trials were of short duration in acute conditions, or for recent onset pain. Only two, in osteoarthritis, investigated efficacy in chronic painful conditions.

All 12 randomised trials that compared dexketoprofen, at any dose, with placebo found dexketoprofen to be statistically superior ( Table 1 ). More common was a comparison of dexketoprofen with an active comparator, which happened in 30 trials. In 29 of these 30 trials, dexketoprofen at the dose used was at least equivalent in efficacy to the comparator drugs with known analgesic efficacy.

Single and Multiple Dose Trials in Dental Pain

Seven randomised trials[22,23,24,25,26,27,28,29] examined the analgesic efficacy of oral dexketoprofen in 994 patients studied in the third molar extraction pain model, 618 of whom received dexketoprofen (Additional file 1). One trial was published as an abstract,[29] with data taken from a clinical trial report.[23] Six of the seven trials were both randomised and double blind, and had quality scores of 4 or 5 of the maximum 5 points and had OPVS scores of at least 9/16. One open trial[27] scored only 1 out of 5.

Three good quality trials were standard pain models reporting pain intensity or pain relief for four to six hours after the initial dose, had patients with moderate or severe pain at entry, and measured pain intensity and pain relief over six hours.[24,25,28] In these three trials dexketoprofen at doses of 10 or 12.5 mg (Figure 1), 20 or 25 mg (Figure 2), and 50 mg were all significantly superior to placebo, with NNTs for at least 50% pain relief over six hours compared with placebo of 3.0 (2.3 to 4.4), 2.6 (2.0 to 3.5), and 2.1 (1.5 to 3.5) respectively ( Table 2 ). One trial[28] used ketoprofen 50 mg, and that was also significantly better than placebo. The one other trial that used placebo[26] reported data at eight hours, and appeared to measure pain scores after use of remedication. Despite that, dexketoprofen 25 mg was significantly better than placebo.

L'Abbé plot of individual trials of dexketoprofen 10/12.5 mg compared with placebo in dental and postsurgical pain. Inset scale shows size of trial. Light symbols = dental trials, dark symbols = postsurgical trials.

L'Abbé plot of individual trials of dexketoprofen 20/25 mg compared with placebo in dental and postsurgical pain. Inset scale shows size of trial. Light symbols = dental trials, dark symbols = postsurgical trials.

Dexketoprofen 12.5 mg and 25 mg were both superior to dipyrone 575 mg in the single dose phase of a multiple dose trial.[22] There was no difference between use of pre and postsurgical dexketoprofen in another trialsup>.[23,29] The final trial[27] compared dexketoprofen 25 mg with ibuprofen 600 mg, but no interpretation could be made in this case because it included patients with mild pain which is known to desensitise pain trials.

Single and Multiple Dose Trials in Postsurgical Pain

Thirteen randomised trials[30,31,32,33,34,35,36,37,38,39,40,41,42,43] examined the analgesic efficacy of dexketoprofen in 2135 patients studied in postsurgical pain, 997 of whom received dexketoprofen (Additional file 2). One trial was published as an abstract[31] with data taken from a clinical trial report.[42] Twelve of the 13 trials were both randomised and double blind, and 11 had quality scores of three or more of the maximum 5 points and at least 9 on an OPVS ( Table 1 ). Eight trials (1212 patients) used oral dexketoprofen and four (923 patients) intramuscular or intravenous dexketoprofen. Eight of the 13 trials were in major orthopaedic surgery (mainly knee and hip surgery), the others involving arthroscopy, bunionectomy, hernias, abdominal hysterectomy, and abdominal surgery.

Two good quality trials were standard pain models reporting pain intensity or pain relief for four to six hours after the initial dose, had patients with moderate or severe pain at entry, and measured pain intensity and pain relief over six hours.[32,34] In these trials oral dexketoprofen at doses of 10 or 12.5 mg (Figure 1) and 20 or 25 mg (Figure 2) were significantly superior to placebo, with NNTs for at least 50% pain relief over six hours compared with placebo of 4.4 (2.8 to 9.7) and 3.7 (2.5 to 7.0) respectively ( Table 2 ). Four of the nine oral trials used placebo, and in these dexketoprofen was significantly better than placebo on at least one measure in three trials,[34,39,43] but not in the fourth.[32] Ketoprofen 50 mg was not significantly better than placebo in the two trials that used it.[32,34]

Where there was an active comparator, dexketoprofen 25 mg appeared to be equivalent to tramadol 50 mg,[42,33] diclofenac 50 mg,[36] and paracetamol 500 mg plus codeine 22.5 mg.[38] Three trials compared dexketoprofen 25 mg with ketoprofen 50 mg; while there was no difference in one small trial,[41] ketoprofen appeared to be less effective in two others.[32,34]

Two trials[35,40] used intramuscular administration of dexketoprofen at doses of 25 mg or 50 mg twice a day, and two[30,37] intravenous administration of 50 mg three times a day, or 50 mg twice a day. Time intervals between doses were 6-8 h and 12 hours in the different studies. Three[35,37,40] made a comparison with placebo, and in all three doses of dexketoprofen were significantly better than placebo on at least one measure of efficacy. All four trials had an active comparator, and dexketoprofen at the dose studied was at least as effective as ketoprofen 100 mg,[30,40] tramadol 100 mg,[37] and diclofenac 75 mg twice a day.[35] There was a suggestion of somewhat better efficacy between three and eight hours, and lower morphine requirements, than diclofenac 75 mg twice a day.[35]

Overall Results of Single Dose Dexketoprofen in Acute Pain, and Comparison With Ketoprofen

Combining three third molar extraction and two postsurgical trials ( Table 2 ) gave NNTs for at least 50% pain relief for 12.5 mg dexketoprofen of 3.5 (2.7 to 4.9), 25 mg dexketoprofen of 3.0 (2.4 to 3.9), and 50 mg dexketoprofen of 2.1 (1.5 to 3.5). The overlapping confidence intervals and formal testing[44] for difference between NNTs showed no statistical difference between 12.5 mg and 25 mg doses.

Several trials used both dexketoprofen and ketoprofen. Table 2 also shows the comparisons between 12.5 mg and 25 mg dexketoprofen and 50 mg ketoprofen, and 50 mg dexketoprofen and 100 mg ketoprofen. While the proportion of patients achieving at least 50% pain relief was consistently higher with dexketoprofen, this did not reach statistical significance with any comparison. However, when 25 mg or 50 mg dexketoprofen were compared with 50 mg or 100 mg ketoprofen (that is, double the dose, Figure 3), statistical significance was achieved, with a number needed to treat of 8.8 (5.1 to 33). That means that for every nine persons treated with 25 mg or 50 mg dexketoprofen, one more would have at least 50% pain relief than if the same nine patients were treated with ketoprofen 50 mg or 100 mg.

L'Abbé plot of individual trials of dexketoprofen compared with double dose of ketoprofen in dental and postsurgical pain. Inset scale shows size of trial. Light symbols = 25 mg vs 50 mg, dark symbols = 50 mg vs 100 mg.

Single Dose Trials in Pain of Renal Colic

Three randomised trials[45,46,47] examined the analgesic efficacy of dexketoprofen 25 mg and 50 mg intramuscularly, and 25 mg and 50 mg intravenously, in 838 patients studied in pain of renal colic, 526 of whom received dexketoprofen (Additional file 3). All of the trials were both randomised and double blind, all had quality scores of three or more of the maximum 5 points and at least 9 points on an OPVS. One trial[45] used intramuscular dexketoprofen and two[46,47] intravenous dexketoprofen.

None of the trials had a placebo control, and all examined efficacy over six hours after a single dose n pain of moderate or severe intensity. Intramuscular dexketoprofen 25 mg and 50 mg were indistinguishable from intramuscular dipyrone 2000 mg.[45] Intravenous dexketoprofen 25 mg or 50 mg were indistinguishable from intravenous dipyrone 2000 mg or more,[46] and intravenous dexketoprofen 50 mg was indistinguishable from intravenous ketoprofen 100 mg.[47]

Multiple Dose Trials in Acute Low Back Pain

Five trials[48,49,50,51,52,53] examined short-term use of dexketoprofen in acute low back pain, generally over about a week (Additional file 4); one was published in German,[50] but data were taken from a clinical trial report.[49] All of the trials were both randomised and double blind, all had quality scores of three or more of the maximum 5 points and at least 9 points on an OPVS. One shorter trial compared 50 mg twice-daily intramuscular dexketoprofen with 75 mg diclofenac in almost 400 patients.[48] Four oral comparisons of dexketoprofen 25 mg three times daily over 4-7 days in patients with pain of acute onset back pain of at least moderate severity showed similar efficacy to diclofenac 150 mg daily,[51] tramadol 150 mg daily,[49,52] and paracetamol 800 mg plus dextropropoxyphene 60 mg daily.[53]

Single and Multiple Dose Trials in Other Acute Painful Conditions

Five randomised trials[54,55,56,57,58] have examined the analgesic efficacy in other acute painful conditions in 796 patients, 428 of whom received oral dexketoprofen, mainly at 25 mg (Additional file 5). All of the trials were both randomised and double blind, all had quality scores of three or more of the maximum 5 points and at least 9 points on an OPVS. Only one trial[54] was placebo controlled, and looked at efficacy of 12.5 mg and 25 mg of dexketoprofen in comparison with 50 mg ketoprofen in 52 women with dysmenorrhoea; all three active treatments were superior to placebo, but not different one from another.

Dexketoprofen 25 mg orally was found to be superior to injections of mepivacaine into the uterine cervix in producing significantly lower pain scores over 30-120 minutes after hysteroscopy[55] as well as being better than 50 mg diclofenac for lower limb injury between 15 and 60 minutes.[56] Over four days there was no difference between three times daily ketoprofen 25 mg or paracetamol 500 mg plus codeine 60 mg in the treatment of ankle sprains.[57] In patients with cancer who developed bone cancer pain of at least moderate intensity, and who had not previously been treated with a continuous regimen of opioids or NSAIDs in the previous 15 days, there was no difference between 25 mg dexketoprofen and 10 mg ketorolac over seven days.[58]

Multiple Dose Trials in Arthritis

Two trials tested dexketoprofen 25 mg three times a day against ketoprofen 150 mg daily and diclofenac 150 mg daily in patients with established arthritis[59,60](Additional file 6). Both trials were randomised and double blind, all had quality scores of three or more of the maximum 5 points and at least 9 points on an OPVS. The trials had a flare design in which patients discontinued previous treatment. Over two or three weeks of treatment there were no differences between dexketoprofen and diclofenac at these doses,[60] though dexketoprofen 75 mg daily was superior to ketoprofen 150 mg daily.[59]

Overall Comparison Between Dexketoprofen and Ketoprofen

The main comparisons between dexketoprofen and ketoprofen occurred within the dental trials and those in postsurgical pain. There were three other comparisons. One comparison of intravenous administration in renal colic showed no difference between dexketoprofen 50 mg and ketoprofen 100 mg.[47] Of the two oral comparisons there was no difference between dexketoprofen 12.5 mg or 25 mg and ketoprofen 50 mg,[54] while the one comparison between 25 mg dexketoprofen with 50 mg ketoprofen in arthritis showed better results for dexketoprofen.[59]

Adverse Events

Additional file 1, Additional file 2, Additional file 3, Additional file 4, Additional file 5, Additional file 6 records adverse events reported in the trials, in terms of the numbers of patients reporting at least one adverse event, all cause withdrawals, and withdrawal due to an adverse event. Adverse event reporting was generally poor. Because trials varied from single dose to three weeks duration, with different routes of administration, drug doses, comparators, and condition, sensible analysis of adverse events were not possible. Because adverse event withdrawal is a significant event, and attempt was made to examine adverse event withdrawal rates in trials where at least two doses of drug were given. Because the rate of adverse event withdrawals is likely to be a function of the number of doses given, these were split by relatively shorted duration studies predominantly less than two days (dental and postsurgical pain) and relatively longer studies predominantly more two days or longer (acute painful conditions, back pain, and arthritis) ( Table 3 ).

The choice of two doses was simply because withdrawal is not really an option after a single dose and is unlikely to be recorded in the same was as in multiple dose studies.

In both comparisons dexketoprofen (all doses) provided the about half the total number of patients ( Table 3 ). Adverse event withdrawal rates were low, at about 2% or below in dental and postsurgical pain, and somewhat higher in trials of longer duration. The adverse event withdrawal rate for dexketoprofen was not out of line with other drugs, though limited numbers prevented any firm conclusions, and statistical tests were not deemed sensible.

No serious adverse events, like gastrointestinal bleeding, myocardial infarction, or death, were reported in any trial.

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